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European Journal of Heart Failure 2005 7(5):899-903; doi:10.1016/j.ejheart.2004.10.023
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© 2005 European Society of Cardiology

Contrast nephropathy post cardiac resynchronization therapy: An under-recognized complication with important morbidity

Peter J. Cowburn, Harshna Patel, Rebecca R. Pipes and John D. Parker*

Mount Sinai Hospital 600 University Avenue, Suite 1609, Toronto, Ontario, Canada, M5G 1X5

* Corresponding author. Tel.: +1 416 586 4794; fax: +1 416 586 8413. E-mial address: jdp{at}ca.inter.net


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Objectives: The aim of the study was to define the incidence of contrast nephropathy in patients undergoing cardiac resynchronization therapy (CRT).

Background: CRT is a promising new treatment for advanced heart failure. It is a technically demanding procedure with a recognized failure/complication rate. Contrast nephropathy is a well-recognized complication of coronary angiography/intervention, but has not been described following CRT.

Methods: We performed a retrospective chart review of patients who had undergone CRT at Mount Sinai Hospital, a tertiary referral center for heart failure management, to define the incidence of contrast nephropathy in patients undergoing CRT. Contrast nephropathy was defined as the occurrence of a 25% or greater increase in serum creatinine within 48 h after contrast administration.

Results: Sixty-eight patients underwent a total of seventy-three procedures between October 1st 2000 and December 31st 2003. Ten patients (14%) developed contrast nephropathy. Three of these patients (4%) required hemofiltration and one died. Patients with creatinine ≥200 µmol/l (2.26mg/dl) were more likely to develop contrast nephropathy than those with creatinine <200 µmol/l (6/14 patients [43%] v 4/59 patients [7%], p<0.01). The mean length of hospital stay post-procedure in patients developing contrast nephropathy was 19±18 (SD) days versus 4±5 days for those patients with stable renal function (p<0.01).

Conclusions: Contrast nephropathy is a frequent, but under-recognized complication of CRT with important morbidity/mortality. The extended hospital stay associated with contrast nephropathy has important clinical and health care implications. Patients and physicians need to be aware of this potential risk.

Key Words: Resynchronization • Nephropathy • Heart failure

Received July 16, 2004; Revised August 29, 2004; Accepted October 15, 2004


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Contrast nephropathy, defined as an elevation in serum creatinine of 25% or greater, is a well-described complication of coronary angiography/intervention. Estimates vary as to the true incidence, from 3.3% [1] to 14.6% [2], though in very high-risk populations an incidence of 50% has been described [3]. Risk factors for the development of contrast nephropathy include existing renal impairment, diabetes mellitus, congestive heart failure, contrast load and mean arterial blood pressure less than 100 mmHg [1–4].

Cardiac resynchronization therapy (CRT) has recently emerged as a promising therapy for patients with severe congestive heart failure (CHF). Implanting the left ventricular (LV) lead usually involves contrast administration to define coronary venous anatomy, but contrast is also commonly used to help identify and hence cannulate the coronary sinus os. Failure to cannulate the coronary sinus is the commonest reason for failure to implant a CRT device [5] Given that there is a high prevalence of renal dysfunction, diabetes and low blood pressure in these CHF patients, the incidence of contrast nephropathy following CRT is likely to be high.

Randomized trials of CRT have demonstrated improved quality of life, functional status and exercise capacity in patients with moderate/severe heart failure and a wide QRS complex [6–8]. Studies also suggest that CRT reduces hospitalization for heart failure and may reduce mortality [9]. The technical challenges of/complications with LV lead placement are well known [7,8,10], however contrast nephropathy has not been reported following CRT. We therefore retrospectively reviewed charts from all patients who have undergone CRT at our own institution, to define the incidence of contrast nephropathy in this high-risk patient population.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusions
 References
 
A retrospective chart review was performed (approved by the Mount Sinai Research Ethics Board) of patients undergoing CRT at Mount Sinai Hospital, Toronto between October 1st 2000 and December 31st 2003. All patients underwent CRT (+/–ICD implantation) by standard transvenous techniques. Patients were pre- and post-hydrated intravenously unless filling pressures were deemed too high. Acetylcysteine, 600 mg twice daily for a total of four doses [11,12], was prescribed at the discretion of the attending physician for patients with pre-existing renal impairment. Diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, spironolactone and other potentially nephrotoxic agents were routinely withheld on the day of the procedure. LV lead placement was performed using pre-shaped guiding sheaths and over the wire leads. Balloon occlusion venograms were performed to identify the optimal site for LV lead placement. The standard contrast agent used was ioversol 350 mgI/ml (OPTIRAY 350), though this was later changed to iodixanol 320 mgI/ml (VISIPAQUE 320) due to the promising data with this agent in reducing the incidence of contrast nephropathy [13]. Contrast nephropathy was defined as an increase in serum creatinine of 25% or greater within 48 h after contrast administration. Data were analyzed according to whether the patients developed contrast nephropathy or not. Additional analyses studied the patient subset with serum creatinine ≥200 µmol/l (2.26 mg/dl) pre-implant.

2.1. Statistics
Between group comparisons of binary variables were compared using Fisher's Exact test. Between group comparisons of continuous variables were made using unpaired t-tests. Data are presented as mean±SD. The data were analyzed using Statview 5.0, SAS Institute, Cary, NC.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusions
 References
 
Sixty-eight patients underwent a total of 73 procedures between October 2000 and August 2003. The 5 additional procedures were for LV lead displacement (2 patients), LV lead repositioning (2 patients, normal pacing function but poor initial clinical response) and a new system implant following local infection. In 5 patients it was not possible to implant the LV lead.

Clinical characteristics are detailed in Table 1.


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  		Table 1 Clinical characteristics of patients undergoing cardiac resynchronization therapy

 
The mean age of patients undergoing CRT was 67 years. All patients were in NYHA class III or IV. The mean outpatient diuretic dose was 141 mg furosemide. 36% of patients were diabetic and 66% had ischemic heart disease. One third of patients undergoing CRT had been admitted on a non-elective basis, typically with decompensated heart failure. The mean baseline creatinine was 151 µmol/l (1.71 mg/dl). Mean left ventricular ejection fraction (LVEF) was 19%. Acetylcysteine was prescribed for 75% of cases (patients were not routinely given acetylcysteine for renal impairment at the start of the program as there was limited research evidence to support its use). Seventy-five percent of cases received intravenous hydration and 36% of patients received iodixanol; all other patients received ioversol.

Ten patients (14%) developed contrast nephropathy. Three of these patients (4%) required hemofiltration: one patient died of progressive heart failure 62 days post-procedure. Another was discharged 26 days post procedure, only to be re-admitted 10 days post-discharge; he died 46 days after attempted CRT. The third patient requiring hemofiltration was discharged 35 days post-procedure and is still alive 9 months post procedure. Renal function recovered in all cases. Nine of the ten patients developing contrast nephropathy had been pre-treated with acetylcysteine. Only 1 of the 5 failed LV lead implants resulted in contrast nephropathy. No procedures were cancelled due to pulmonary edema due to intravenous fluid administration.

Patients developing contrast nephropathy had worse baseline renal function (creatinine 191±53 µmol/l [2.16±0.60 mg/dl]) when compared with patients whose renal function remained stable (mean creatinine 144±42 µmol/l [1.63±0.48 mg/dl]; p<0.01). Patients developing contrast nephropathy also had higher systolic pulmonary artery pressures as assessed non-invasively when compared with patients with maintained renal function (56±6 mmHg versus 48±11 mmHg, p<0.05). Patients developing contrast nephropathy had a markedly extended hospitalization post procedure when compared with patients whose renal function did not deteriorate (19±18 days versus 4±5 days, respectively, p<0.01).

Data were further analyzed according to baseline renal function. Fourteen patients had a creatinine ≥200 µmol/l (2.26mg/dl); of these six (43%) developed contrast nephropathy whereas only 4 out of 59 patients (7%) with creatinine <200 µmol/l developed contrast nephropathy (p<0.01). Patients with creatinine ≥200 µmol/l were older (74±7 years versus 65±13 years, p<0.05) and more likely to have ischemic heart disease (86% versus 61%, p<0.05). Left ventricular end-diastolic dimension (LVEDD) was actually greater in the creatinine <200 µmol/l group (71±11 versus 64±9 mm, p<0.05); there were no other significant baseline differences between the two groups (Table 2). Hospital stay was markedly extended in patients with creatinine ≥200 µmol/l (16±18 days versus 4±3 days, p<0.01) irrespective of the development of contrast nephropathy.


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  		Table 2 Clinical characteristics/outcome of CRT based on pre-procedure creatinine

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusions
 References
 
We have demonstrated that there is a high incidence of contrast nephropathy in patients undergoing CRT. This was despite taking care to minimize patient risk by the use of intravenous fluids, acetylcysteine [11,12] and more recently, the use of an iso-osmolar non-ionic contrast medium [13]. This decline in renal function has important clinical and health care implications, with an associated increase in hospital stay. It is of note that the risk of contrast nephropathy in this study is significantly higher than the more frequently quoted complications of CRT [7,8,10].

Severe renal dysfunction and higher pulmonary artery pressures characterized the population that developed contrast nephropathy. Contrast volumes were generally greater in patients developing contrast nephropathy, but this was not statistically significant as three patients developed contrast nephropathy following small contrast loads (45, 60 and 65 ml, respectively). The three patients developing contrast nephropathy with contrast volumes of <100 ml all had a baseline creatinine of ≥200 µmol/l (2.26 mg/dl) and 2 of these patients were receiving inotropic support. The lack of statistical significance may also be as a result of a relatively small study population. Our mean contrast volume used was 146 ml. While only small quantities of contrast are required to perform coronary sinus venograms, larger contrast volumes may be used when there is difficulty finding/cannulating the coronary sinus.

We have also demonstrated that patients undergoing CRT with a baseline creatinine ≥200 µmol/l (2.26 mg/dl) are at increased risk of contrast nephropathy (43% risk versus 7% risk for creatinine <200 µmol/l group, p<0.01), and, irrespective of the development of contrast nephropathy, patients with a creatinine ≥200 µmol/l have an extended hospitalization post procedure. This finding concurs with a previous study demonstrating adverse outcomes for patients with renal impairment undergoing percutaneous intervention [14].

We believe our group of patients is representative of typical patients undergoing CRT. Patients participating in the MIRACLE study had a mean age of 64, a mean left ventricular ejection fraction (LVEF) of 22% and a mean LVEDD of 70 mm [7]. Patients in our own study had a mean age of 67, a mean LVEF of 19% and a mean LVEDD of 69 mm. However, unlike MIRACLE, a number of our patients underwent CRT on a non-elective admission (usually during an admission with decompensated CHF); these patients did not have an increased risk of contrast nephropathy (8% risk).

Our incidence of contrast nephropathy is in keeping with other published data. McCullough et al. reported a 14.5% incidence of contrast nephropathy in patients undergoing coronary intervention with a mean creatinine of 1.3 mg/dl (115 µmol/l) and a mean LVEF of 48% [2]. Gruberg et al. studied patients with a baseline serum creatinine of >1.8 mg/dl [159 µmol/l] (mean LVEF of 39%) undergoing coronary intervention [16]. In this series 37% of patients developed contrast nephropathy and 7.1% of all patients required dialysis [16]. The mean contrast volumes used in these two reports were 248 ml and ~230 ml respectively [2,16]. The in-hospital mortality for patients requiring dialysis in these trials was 35.7% and 22.6% respectively [2,16].

Our results therefore are not surprising; stated simply we have confirmed that contrast administration to high-risk patients may cause contrast nephropathy. What is a surprise, however, is that contrast nephropathy has not been previously reported as an important procedural complication in patients undergoing CRT, when in our practice it is the most common procedure related complication observed. It is possible that we studied a patient population with higher diuretic requirements and renal function that was worse than found in the clinical trials, and indeed it does seem from our data that patients with creatinine >200 µmol/l (2.26 mg/dl) have a particularly poor outcome. However, none of our patients had a creatinine above 3.0 mg/dl (265 µmol/l), which was one of the exclusion criteria for the MIRACLE and MIRACLE ICD trials [7,8]. Our mean contrast volume was 146 ml, however this is not different from the mean contrast volume of 169 ml reported by Meisel et al. in performing coronary sinus venography in 129 patients undergoing ICD implantation [15].

Methods to reduce contrast nephropathy should focus both on reducing contrast load and optimizing patient preparation for CRT. In our own center we transduce pressure waveforms from the coronary sinus guide catheter to avoid unnecessary test injections of contrast whilst in the right ventricle. Another option is to use EP electrode catheters to identify the coronary sinus without the use of contrast. When patients are undergoing coronary angiography prior to CRT we now acquire levophase views of the coronary sinus in the antero–posterior and left anterior oblique projections to define the take-off of the coronary sinus. We believe that high quality balloon occlusion venograms at the time of coronary sinus cannulation are essential to define all potential veins for lead placement. Three views can usually be taken with less than 20 ml contrast. The excess loads of contrast tend to be given only when there is difficulty cannulating the coronary sinus.

Adequate hydration is important, particularly in patients with a high baseline creatinine. As this can be hard to assess clinically, all our patients now undergo right heart catheterisation to define filling pressures as part of their work up prior to CRT. All patients now receive normal saline pre-procedure at 1 ml/kg/h if filling pressures are low, or at 0.5 ml/kg/h if filling pressures are high. In patients with high baseline creatinine we now routinely measure right heart pressures at the time of performing CRT. Once the right-sided leads have been secured, we pass a Swan–Ganz catheter via the coronary sinus guide catheter to measure pulmonary artery pressure and pulmonary capillary wedge pressure. Accurately knowing filling pressures helps guide post-operative intravenous fluid and diuretic administration. We now pre-treat all patients with a creatinine >100 µmol/l with acetylcysteine [11,12] and use a non-ionic iso-osmolar contrast agent (iodixanol) for all cases [13].


   5. Conclusions
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
References
 
Contrast nephropathy is a frequent, but under-recognized, complication of CRT, with important morbidity/mortality. When considering patients for CRT, patients and physicians need to be aware of this potential complication. Strenuous efforts are required to reduce patient risk, by minimizing contrast administration and implementing measures for renal protection. In high-risk patients, invasive hemodynamic assessment should be considered to allow optimal hydration.


   Acknowledgements
 
Dr Cowburn is supported by travel grants from the Peel Medical Research Trust and Wessex Heartbeat.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 

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